DESCRIPTION: Adenine nucleotides, released from neurons and other cell types regulate a broad range of physiological responses through P2-purinergic receptors (P2-R). The PI and his collaborators were the first to identify a uridine nucleotide specific P2-R and have also identified a P2R receptor that inhibits adenylyl cyclase by activating Gi. In addition, the PI has cloned the genes coding for several P2Rs and has identified several novel receptors whose genes have not yet been cloned. Through collaborative efforts novel competitive P2R antagonists and P2Y subtype-specific agonists have been synthesized and characterized. The PI wishes to capitalize on these advances to: (1) conduct structure/function relationships on the nucleotide binding domain by making chimeras and site-directed mutants (2) continue the process of identifying and characterizing novel ligands for P2-Rs and (3) clone, sequence and express the novel G-protein-coupled (GPC) P2-Rs that the PI and his colleagues have identified pharmacologically so their second messenger specificity and detailed pharmacology can be analyzed. Since so little is known concerning P2R receptors, this approach which combines ligand development, cloning, pharmacological characterization and mutagenesis to determine amino acids involved in ligand binding should provide new knowledge concerning the structure(s) and mechanism(s) of this class of GPCRs and lead to the development of subtype-specific therapeutic agents.